Androstano[3,2-c]-5&#39;-hydroxy-delta2&#39;-isoxazolines and the preparation thereof



United States Patent 3,100,771 ANDRQSTANOB ,2-c1-5 '-HYDR0XY-A -ISOXAZ0- LINES AND THE PREPARATION THEREOF Andrew John Manson, North Greeubush, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware 1 No Drawing. Filed Aug. 10, 1962, Ser. No. 216,076 6 Claims. (Cl. 260-23955) This invention relates to new heterocyclic steroids and in particular is concerned with androstano[3,2 -c ]-'-hydroxy-A isoxazolines and the preparation thereof.

The compounds of the invention have the structural formula l R CH 3 wherein R and R" are selected from the group consisting of hydrogen and carboxylic acyl radicals having from one to ten carbon atoms and a molecular weight less than 200; and R is selected from the group consisting of hydrogen, lower-alkyl and lower-alkynyl.

It has been found that the reaction of a steroid having the formula with hydroxylamine in lower-alkanol solution at approximately neutral pH produces three products, a steroido- HOCH [2,3-d1isoxazole, a steroido[3,2-c]isoxazole, and a ste-.

roido[3,2-c] -5'-hydroxy-A '-isoxazoline of Formula .I (R

and R are H). The last named compound can be sepa-.

rated from the mixture of products as the least soluble component in a non-polar organic solvent. The approximately neutral pH is obtained by using hydroxylamine in the form of its hydrochloride salt and buffering the latter with approximately one equivalent of an alkali metal salt of a weak acid such as sodium or potassium acetate. The non-polar organic solvent can be any such solvent in which the product mixture is at least "slightly soluble. Ethyl acetate has been found to be a particularly satisfactory solvent for fractional crystallization of the R are carboxylic acyl radicals said acyl radicals 'are preferably derived from carboxylic acids having from one to about ten carbon atoms, conventionally employed in the steroid art, and having a molecular weight less than about 200. Representative of the acyl radicals which can be present are lower-alkanoyl radicals, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl, trimethylacetyl, and the like; carboxy-loweralkanoyl radicals, e.g., succinyl (B-carboxypropionyl); cycloalkyl-lower-alkanoyl radicals, e.g., ,B-cyclop'entyh propiony-l, fi-cyclohexylpropionyl, and the like; monocarbocyclic aroyl radicals, e.g., benzoyl, p-toluyl, p-nitrobenzoyl, 3,4,5-trimethoxybenzoyl, and the like; monocarbocyclic aryl-lower-alkanoyl or -alkenoyl radicals, such as phenylacetyl, ii-phenylpropionyl, cinnamoyl, and the like; and monocarbocyclic aryloxy-lower-alkanoyl radicals, such as p-chlorophenoxyacetyl, and the like. The acylated compounds are prepared by conventional esterification procedures, as by reaction of the corresponding carbinols with the appropriate acid anhydride or acid halide in the presence of pyridine. The 5-hydroxy group and 17-hydroxy group (R' is hydrogen) esterify readily upon heating at a temperature of 100 C. or lower for a brief period (about one hour). In order to prepare esters of the 17-hydroxy group (R is lower-alkyl) more stringent conditions are needed (reflux temperature). In the latter case some dehydration to the isoxazole may occur but the desired bis-ester may be separated by physical methods. The resulting bis-ester (I; R and- R are acyl, R is lower-alkyl) can be selectively saponified to prepare a l7-mono ester (I; R is H, R is acyl, R is lower-alkyl) The structures of the compounds of Formula I were assigned on the basis of elementary analysis and infrared and nuclear magnetic resonance (NMR) spectra, 'as well as from the factthat upon dehydration they are converted to isoxazolesp For example, 17 3-hydroxy-l7m-methylandrostano[3,2-c]5-hydroxy-A '-isoxazoline (I; R is ,H, R is methyl, R is H) upon treatment with a catalytic amount of concentrated hydrochloric acid in boiling acetic acid solution, loses two molecules of water and is converted quantitatively to 17,17-dirnethyl-l8-norl3- androsteno[3,2-c1isoxazole. The structure of the latter was firmly established by ultraviolet, infrared and NMR spectra. The. stereochemical assignments are based on conformational analysis. and relative difliculty of dehydration of the 5'-hydroxy group.

Endocrinological studies of the compounds of the invention have shown that they possess useful metabolic and hormonal properties; In particular they have been found toliave pituitary inhibiting, anabolic and myotropic activity. The compounds of the invention can be prepared for use by disp'ersing them in an. aqueous suspension or by dissolving them in a pharmacologically l-butyuyl and the t acceptable oil or oil-water emulsion for parenteral administration; or by incorporation in tablet form with excipients for oral administration; 1

The compounds of the invention are also useful as intermediates for preparing steroido[3,2-c1isoxazoles by dehydratiom The following examples Will further illustrate the invention without the latter being limited thereby.

[QR is 3.11 is CH5, R" is H] v i To a solution of 10.0 g. of Z-hydroxymethylene-lhrhethylaudrostan-l'ZB-ol-B-one, M.P. l62l77 Cy, in 300 ml. of ethanol was added a solu-tion of 2.09 g. of hydroxylarnine hydrochloride and 3.88 g. of sodium acetate trihydrate inlO ml. of water. The resultant solution was boiled under reflux for four hours and then concentrated under reduced pressure to a volume of 50 ml. Water Patented Aug. 13, 1963.

. Z1 and ethyl acetatewere added to the residue, the layers separated, and-the aqueouslayer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to a volume of 100 ml.

from the solution. 2.58 g. of product which was separated and recrystallizedseveral times from ethyl acetate to give 1.52 g. of 17fl-hydroxy-17a methylandrostano-[3, 2 c]- hydroxy-A l-isoxazoline in the form of colorless needles, M.P. 2352-2402 C. (corn), [a] =138.5 (1% in chloroform); infrared absorption at 3.10, 3.44, 6.14 and 6.19 7

EXAMPLE 2 17,6-Hydroxy-1 7 a-M elhylandrostano [3,2-c] -5 -A cetoxy- 1 MJsoxazoline l V [I; R is CGCH R is CH R is H] Asolution of 10.0 g. of 17,8-hydroxy-17a-methylandros'tano[3,2-c] -5-hydroxy-A -isoxazoline (Example 1) and 7.5 ml. of acetic anhydride in 100 ml. of pyridine was heated on a steam bath for 75 minutes. The reaction mixture'was diluted with 1 liter of water andextracted with ether. The ethereal extract was dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residual oil was crystallized from 30 ml. of ether to give 2.21 g. of colorless needles, M.P. 166-172 C. The residual material from the mother liquor was subjected to chromatography on 360 g. of Florisil (activated magnesium silicate). Elution. with 7:3 pentaneether gave several crystalline fractions. The center frac-1 tions (3.12 g.) were combined and recrystallized from ether. There was obtained 2.66 g. of colorless needles, M.P. 170-173 C., 'undepressed on admixture with the above crop of 2.21 g. Recrystallization from ether gave pure l7fl-hydroxy 170a methylandrostano[3,2-c]-5-acetoxy-A -isoxazoline, M.P. 167.2169.2 C. (corn),

[a] '=--2'69.2' (1 in chloroform), infrared absorption at 2.81, 3.45, 5.69, 6.90 and 8.24 4; NMR spectrum: signals at 6.88 (doublet), 262,175, 1.53 and 1.40 ppm. Similarly 17/3-hydroxy 17u-rnethylandrostano[3,2-c]-5- hydroxy-Mdsoxazoline can be caused to react with pro pionicanhydride, caproyl chloride, [i-cyclopentylpropionyl I chloride, benzoyl chloride, p-nitrobenzoyl chloride, 3,4,5

trimethoxybenzoyl chloride, phenylacetyl chloride, cinnamoyl chloride, or p-chlorophenoxyacetyl chloride, to give, respectively, 17,8-hydroxyl7a methylandrostano- [3,2-c]-5-pr-opionoxy-A -isoxazoline (I; R is COCH CH Ris CH R" is H], 17,8-hydroxy-17or-methylandrostano- [3,2-c]-5-caproyloxy-A -isoxazoline [1; R is 1 R is H], 17fi-hydroxy-17a-methylandrostano[3,2-c]-5'- cinnamoyloxy-M'dsoxazoline [1; R is COCH-CHC H R is. CH R is H], or 17/3-hydroxy-l7a-methylandrostano 3 ,2c] -5 4-.chlorophenoxyacetoxy) -A -isoxazoline [I; R is COCH OC H Cl-4, R is CH5, R'is H].

When 17,8-hydroxy 17a methylandrostano[3,2-c]-5'- hydroxy-A?-isoxazoline was heated to reflux temperature in acetic -anhydride solution there was produced a product mixture containing 17,8-acetoxy-l7a-rnethylandro-.

stano[3,2-c] 5-acetoxy-A isdxazolihe [I; R is COCH R".1s COCH and 17p-acetoxy-l7rx-methylandrostano- V [3,2-c.]isoxazole.

'Upon cooling, there crystallized i 4 EXAMPLE '3 I 1713'- hydroxyandrostano[3,2-c] 5 hydroxy -A "-isoxazoline [I; R is H, R is H, R- is H] was'prepared from 3.78 g. of Z-hydroxymethyleneandrostan-l7fi-ol-3-one and 0.825 g. of hydroxylamine hydrochloride. There was obtained 1.31 g. of '17fl=hydroxyandrostano[3,2-c]-5'-hydroxy-A -isoxazoline, prisms, M.P. 245-25 3- C. (uncorn, dec.) when recrystallized from methanol and from acetone; infrared absorption at 2.95, 3.05, 3.44, 6.01, 6.81 and 6.90;. f f

17(3-hydroxyandrostano[3,2 c] -5-hydroxy-A -isoxazoline when caused to react with acetic 'anhydride in pyridine according to the procedure descrihedabove in Example 2 yields 17,8-aeetoxy-a11drostano[3,2 c]-5-acetoxy-A aisoxazoline- [I; R is COCH R" isH, R is COCH v By replacement of the Z-hydroxyniethylen-Not-methylandrostan-17fl-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene-l7a-ethylandrostan- 17/3-ol-3-one, 2 hydroxymethylene-l7a-propylandrostan 17fl-ol-3-one, 2-hydroxyrnethylene l7 x isopropylandrostan-17fi-ol-3-one, Z-hydroxymethylene 17a butylandrostan-l7fi-ol-3-one, 2-hydroxymethylene-17a-ethynylandrostan-l7/3-ol-3-one, or 2-hydroxymethylene-l7u-propargylandrost an-17fl-ol-3-one, there can be obtained, respectively, 17,8 hydroxy a ethylandrcstano [3,2-c ]-5-hy droxy-Mdsoxazoline [R is H, R is C H R" is H], 17B-hydroxy 170a propylandrostano[3,2-c]-5-hydroxy- A -isoXazoline [R is H, R is (CH CH R is H], 176 hydroxy 17a isopropylandrostano[3,2-c]l- 5' hydroxy-Mdsoxazoline [R is H, R is' CH(CH R is H], 17,8-hydroxy-17ot-butyla-ndrostano [3,2-c] -5-hydroxya; I 0/ \K t 0 wherein R and R are selected from the group consisting of. hydrogen and carboxylic acyl radicals having from one to ten carbon atoms and a molecular weight less than 200; and R is selected from the group consisting of hydrogen, lower-alkyl and low'er-alkynyl. 2. l7fl-hydroxy 170a methylandrostano[3,2'-c]-5-hy droxy-A -isoxazoline. 3. l7fl-hydroxy 170: methylandrostano[3,2-.c]-5-acetoxy-d isoxazoline.

4. 171% -hydroxyandro'stano[3,2 c] 5 hydroxy-A isoxazoline.

-5. The process for preparing a compound of the formula wherein R.is selectedfrom the group consisting ofhydro- HO-CH:

withhydroxylamine in lower-alkanol solution at approximately neutral pH, and separating the component of the product mixture least soluble in a non-polar organic solvent.

6. The process for preparing 17B-hydroxy-17a-methylandrostano[3,2-c]-5-hydroxy-A -isoXazoline which comprises reacting 2-hydroxymethylene-17a-methylandrostan- 17B-01-3-0ne with hydroxylamine in lower-alkanol solution at approximately neutral pH, and separating the component of the product mixture least soluble in a non-polar organic solvent.

No references cited. 

1. A COMPOUND OF THE FORMULA 